Increased Remyelination and Proregenerative Microglia Under Siponimod Therapy in Mechanistic Models

Abstract

Background and ObjectivesSiponimod is an oral, selective sphingosine-1-phosphate receptor-1/5 modulator approved for treatment of multiple sclerosis.MethodsMouse MRI was used to investigate remyelination in the cuprizone model. We then used a conditional demyelination Xenopus laevis model to assess the dose-response of siponimod on remyelination. In experimental autoimmune encephalomyelitis–optic neuritis (EAEON) in C57Bl/6J mice, we monitored the retinal thickness and the visual acuity using optical coherence tomography and optomotor response. Optic nerve inflammatory infiltrates, demyelination, and microglial and oligodendroglial differentiation were assessed by immunohistochemistry, quantitative real-time PCR, and bulk RNA sequencing.ResultsAn increased remyelination was observed in the cuprizone model. Siponimod treatment of demyelinated tadpoles improved remyelination in comparison to control in a bell-shaped dose-response curve. Siponimod in the EAEON model attenuated the clinical score, reduced the retinal degeneration, and improved the visual function after prophylactic and therapeutic treatment, also in a bell-shaped manner. Inflammatory infiltrates and demyelination of the optic nerve were reduced, the latter even after therapeutic treatment, which also shifted microglial differentiation to a promyelinating phenotype.DiscussionThese results confirm the immunomodulatory effects of siponimod and suggest additional regenerative and promyelinating effects, which follow the dynamics of a bell-shaped curve with high being less efficient than low concentrations.

Siponimod ameliorates metabolic oligodendrocyte injury via the sphingosine-1 phosphate receptor 5

“…Dietrich et al. recently demonstrated that siponimod can support remyelination, presumably by modulating the polarization of microglia cells ( 45 ).…”

Updates and Advances in Multiple Sclerosis Neurotherapeutics

“…In addition to siponimod’s effects on the inflammatory and neurodegenerative components of MS, preclinical data also indicated that its neuroprotective mechanisms could include attenuation of axonal demyelination and promotion of axonal remyelination via oligodendrocytes [ 29 ]. Further, Jackson et al demonstrated that after insult was elicited by lysophosphotidyl choline in a rat model, fingolimod could also actively promote remyelination, suggesting a direct interaction of fingolimod with microglia, oligodendrocytes and/or astrocytes [ 30 ].…”

The Two Sides of Siponimod: Evidence for Brain and Immune Mechanisms in Multiple Sclerosis

“…Treatment with siponimod 5 days after adoptive transfer resulted in a sparing of myelin compared with untreated controls, but with no change in oligodendrocyte numbers [ 81 ]. A study utilizing three experimental models (cuprizone and autoimmune encephalomyelitis-optic neuritis mouse models and a conditional demyelination Xenopus tadpole model) observed a protective effect of siponimod on oligodendrocytes [ 82 ]. Finally, post hoc analyses of MRI data from the phase 3 EXPAND trial also suggest that siponimod might have a beneficial effect on myelination density in patients with SPMS (see Sect.…”

“…Basal levels of receptor gene expression are highest for S1P 1 , followed by S1P 5 , and then the other S1P receptors [ 58 ], although experimental or disease conditions can alter expression levels. Beneficial effects of siponimod in the CNS driven by shifting microglia to a regenerative state have been found [ 82 ].…”